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Genetics and Human Malleability
By W. French Anderson
Just how much can, and should we change human nature by genetic engineering? Our response to
that hinges on the answers to three further questions: (1) What can we do now? Or more
precisely, what are we doing now in the area of human genetic engineering? (2) What will we be
able to do? In other words, what technical advances are we likely to achieve over the next five to
ten years? (3) What should we do? I will argue that a line can be drawn and should be drawn to
use gene transfer only for the treatment of serious disease, and not for any other purpose. Gene
transfer should never be undertaken in an attempt to enhance or "improve" human beings.
What Can We Do?
In 1980 John Fletcher and I published a paper in the New England Journal of Medicine in which
we delineated what would be necessary before it would be ethical to carry out human gene
therapy. As with any other new therapeutic procedure the fundamental principle is that it should
be determined in advance that the probable benefits outweigh the probable risks. We analyzed the
risk benefit determination for somatic cell gene therapy and proposed three questions that need to
have been answered from prior animal experimentation: Can the new gene be inserted stably into
the correct target cells? Will the new gene be expressed (that is, function) in the cells at an
appropriate level? Will the new gene harm the cell or the animal? These criteria are very similar to
those required before use of any new therapeutic procedure, surgical operation, or drug. They
simply require that the new treatment should get to the area of disease, correct it, and do more
good than harm.
Somatic cell gene therapy for the treatment of severe disease is considered ethical because it can be
supported by the fundamental moral principle of beneficence: It would relieve human suffering…
Under what circumstances would human genetic engineering not be a moral good? In the broadest
sense, when it detracts from, rather than contributes to, the dignity of man.
A great deal of scientific progress has occurred in the nine years since that paper was published.
The technology does now exist for inserting genes into some types of target cells. The procedure
being used is called “retroviral-mediated gene transfer." In brief, a disabled murine retrovirus
serves as a delivery vehicle for transporting a gene into a population of cells that have been
removed from a patient. The gene-engineered cells are then returned to the patient.
The first clinical application of this procedure was approved by the National Institutes of Health
and the Food and Drug Administration on January 19, 1989. Our protocol received the most
thorough prior review of any clinical protocol in history: It was approved only after being
reviewed fifteen times by seven different regulatory bodies. In the end it received unanimous
approval from every one of those committees. But the simple fact that the NIH and FDA, as well
as the public, felt that the protocol needed such extensive review demonstrates that the concept of
gene therapy raises serious concerns.
We can answer our initial question, "What can we do now in the area of human genetic
engineering?” by examining this approved clinical protocol. Gene transfer is used to mark
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cancer-fighting cells in the body as a way of better understanding a new form of cancer therapy.
The cancer-fighting cells are called TIL (tumor-infiltrating-lymphocytes), and are isolated from a
patient's own tumor, grown up to a large number, and then given back to the patient along with
one of the body's immune growth factors, a molecule called interleukin 2 (IL-2). The procedure,
developed by Steven Rosenberg of the NIH, is known to help about half the patients created.
The difficulty is that there is at present no way to study the TIL once they are returned to the
patient to determine why they work when they do work (that is, kill cancer cells), and why they
do not work when they do not work. The goal of the gene transfer protocol was to put a label on
the infused TIL, that is, to mark these cells so that they could be studied in blood and tumor
specimens from the patient over time.
The TIL were marked with a vector (called N2) containing a bacterial gene that could be easily
identified through recombinant DNA techniques. Our protocol was called, therefore, the N2-TIL
Human Gene Transfer Clinical Protocol. The first patient received gene-marked TIL on May 22,
1989. Five patients have now received marked cells. No side effects or problems have thus far
arisen from the gene transfer portion of the therapy. Useful data on the fate of the gene-marked
TIL are being obtained.
But what was done that was new? Simply, a single gene was inserted into a population of cells
that had been obtained from a patient's body. There are an estimated 100,000 genes in every
human cell. Therefore the actual addition of material was extremely minute; nothing to
correspond to the fears expressed by some that human beings, would be "reengineered."
Nonetheless, a functioning piece of genetic material was successfully inserted into human cells and
the gene-engineered cells did survive in human patients.
What Will We Be Able to Do?
Although only one clinical protocol is presently being conducted, it is clear that there are several
applications for gene transfer that probably will be carried out over the next five to ten years.
Many genetic diseases that are caused by a defect in a single gene should be treatable, such as
ADA deficiency (a severe immune deficiency disease of children), sickle cell anemia, hemophilia,
and Gaucher disease. Some types of cancer, viral diseases such as AIDS, and some forms of
cardiovascular disease are targets for Treatment by gene therapy. In addition, germline gene
therapy, that is, the insertion of a gene into the reproductive cells of a patient, will probably be
technically possible in the foreseeable future. My position on the ethics of germline gene therapy
is published elsewhere.
But successful somatic cell gene therapy also opens the door for enhancement genetic
engineering, that is, for supplying a specific characteristic that individuals might want for
themselves (somatic cell engineering) or their children (germ-line engineering) which would not
involve the treatment of a disease. The most obvious example at the moment would be the
insertion of a growth hormone gene into a normal child in the hope that this would make the child
grow larger. Should parents be allowed to choose (if the science should ever make it possible)
whatever useful characteristics they wish for their children?
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What Should We Do?
A line can and should be drawn between somatic cell gene therapy and enhancement genetic
engineering. Our society has repeatedly demonstrated that it can draw a line in biochemical
research when necessary. The Belmont Report illustrates how guidelines were formulated to
delineate ethical from unethical clinical research and to distinguish clinical research from clinical
practice. Our responsibility is to determine how and where to draw lines with respect to genetic
engineering.
Somatic cell gene therapy for the treatment of severe disease is considered ethical because it can
be supported by the fundamental moral principle of beneficence: It would relieve human suffering.
Gene Therapy would be, therefore, a moral good. Under what circumstances would human
genetic engineering not be a morally good? In the broadest sense, when it detracts from, rather
than contributes to, the dignity of man. Whether viewed from a theological perspective or a
secular humanist one, the justification for drawing a line is founded on the argument that, beyond
the line, human values that our society considers important for the dignity of man would be
significantly threatened.
Somatic cell enhancement engineering would threaten important human values in two ways: It
could be medically hazardous, in that the risks could exceed the potential benefits and the
procedure therefore cause harm. And it would be morally precarious, in that it would require
moral decisions our society is not now prepared to make, and it could lead to an increase in
inequality and discriminatory practices.
Medicine is a very inexact science. We understand roughly how a simple gene works and that
there are many thousands of housekeeping genes, that is, genes that do the job of running a cell.
We predict that there are genes which make regulatory messages that are involved in the overall
control and regulation of the many housekeeping genes. Yet we have only limited understanding
of how a body organ develops into the size and shape it does. We know many things about how
the central nervous system works for example, we are beginning to comprehend how molecules
are involved in electric circuits, in memory storage, in transmission of signals. But we are a long
way from understanding thought and consciousness. And we are even further from understanding
the spiritual side of our existence.
Even though we do not understand how a thinking, loving, interacting organism can be derived
from its molecules, we are approaching the time when we can change some of those molecules.
Might there be genes that influence the brain's organization or structure or metabolism or circuitry
in some way so as to allow abstract thinking, contemplation of good and evil, fear of death, awe
of a 'God'? What if in our innocent attempts to improve our genetic make-up we alter one or more
of those genes? Could we test for the alteration? Certainly not at present. If we caused a problem
that would affect the individual or his or her offspring, could we repair the damage? Certainly not
at present. Every parent who has several children knows that some babies accept and give more
affection than others, in the same environment. Do genes control this? What if these genes were
accidentally altered? How would we even know if such a gene were altered?
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My concern is that, at this point in the development of our culture's scientific expertise, we might
be like the young boy who loves to take things apart. He is bright enough to disassemble a watch,
and maybe even bright enough to get it back together again so that it works. But what if he tries
to "improve" it? Maybe put on bigger hands so that the time can be read more easily. But if the
hands are too heavy for the mechanism, the watch will run slowly, erratically, or not at all. The
boy can understand what is visible, but he cannot comprehend the precise engineering calculations
that determined exactly how strong each spring should be, why the gears interact in the ways that
they do, etc. Attempts on his part to improve the watch will probably only harm it. We are now
able to provide a new gene so that a property involved in a human life would be changed, for
example, a growth hormone gene. If we were to do so simply because we could, I fear we would
be like that young boy who changed the watch's hands. We, too, do not really understand what
makes the object we are tinkering with tink.
In summary, it could be harmful to insert a gene into humans. In somatic cell gene therapy for an
already existing disease the potential benefits could outweigh the risks. In enhancement
engineering, however, the risks would be greater while the benefits would be considerably less
clear.
Yet even aside from the medical risks, somatic cell enhancement engineering should not be
performed because it would be morally precarious. Let us assume that there were no medical risks
at all from somatic cell enhancement engineering. There would still be reasons for objecting to this
procedure. To illustrate, let us consider some examples. What if a human gene were cloned that
could produce a brain chemical resulting in markedly increased memory capacity in monkeys after
gene transfer? Should a person be allowed to receive such a gene on request? Should a pubescent
adolescent whose parents are both five feet tall be provided with a growth hormone gene on
request? Should a worker who is continually exposed to an industrial toxin receive a gene to give
him resistance on his or his employer's request?
These scenarios suggest three problems that would be difficult to resolve: what genes should be
provided, who should receive a gene, and how to prevent discrimination against individuals who
do or do not receive a gene.
We allow that it would be ethically appropriate to use somatic cell gene therapy for treatment of
serious disease. But what distinguishes a serious disease from a "minor" disease from cultural
"discomfort"? What is suffering? What is significant suffering? Does the absence of growth
hormone that results in a growth limitation to two feet in height represent a genetic disease? What
about a limitation to a height of four feet, to five feet? Each observer might draw the lines
between serious disease, minor disease, and genetic variation differently. But all can agree that
there are extreme cases that produce significant suffering and premature death. Here then is where
an initial line should be drawn for determining what genes should be provided treatment of serious
disease.
If the position is established that only patients suffering from serious diseases are candidates for
gene insertion, then the issues of patient selection are no different than in other medical situations:
the determination is based on medical need within a supply and demand framework. But if the use
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of gene transfer extends to allow a normal individual to acquire, for example, a
memory-enhancing gene, profound problems would result. On what basis is the decision made to
allow one individual to receive the gene but not another: Should it go to those best able to benefit
society (the smartest already?) To those most in need (those with low intelligence? But how low?
Will enhancing memory help a mentally retarded child?)? To those chosen by a lottery? To those
who can afford to pay? As long as our society lacks a significant consensus about these answers,
the best way to make equitable decisions in this case should be to base them on the seriousness of
the objective medical need, rather than on the personal wishes or resources of an individual.
Discrimination can occur in many forms. If individuals are carriers of a disease (for example,
sickle cell anemia), would they be pressured to be treated) Would they have difficulty in obtaining
health insurance unless they agreed to be treated? These are ethical issues raised also by genetic
screening and by the Human Genome project. But the concerns would become even more
troublesome if there were the possibility for “correction" by the use of human genetic engineering.
Finally, we must face the issue of eugenics, the attempt to make hereditary "improvements." The
abuse of power that societies have historically demonstrated in the pursuit of eugenic goals is well
documented. Might we slide into a new age of eugenic thinking by starting with small
"improvements"? It would be difficult, if not impossible, to determine where to draw a line once
enhancement engineering had begun. Therefore, gene transfer should be used only for the
treatment of serious disease and not for putative improvements.
Our society is comfortable with the use of genetic engineering to treat individuals with serious
disease. On medical and ethical grounds we should draw a line excluding any form of
enhancement engineering. We should not step over the line that delineates treatment from
enhancement.
References
1. W. French Anderson and John C. Fletcher, “Gene Therapy in Human Beings: When Is It
Ethical to Begin?," New England Journal of Medicine 303:22 (1980), 1293-97.
2. See also W. French Anderson, "Prospects for Human Gene Therapy," Science, 26 October
1984. 401-409. I. Friedman "Progress towards Human Gene Therapy,” Science, 16 June
1989, 1275-81.
3. J. Wyngaarden, "Human Gene Transfer Protocol,” Federal Register (1989) vol. 54 no. 47.
pp. 10508-10510.
4. Steven A. Rosenberg et al. "Use of Tumor-infiltrating Lymphocytes and Interleukin-2 in the
Immunotherapy of Patients with Metastatic Melanoma,” New England Journal of
Medicine 319:25 (1988), 1676-80.
5. W. French Anderson, "Human Gene Therapy: Scientific and Ethical Considerations," Journal
of Medicine and Philosophy 10 (1985): 275-91.
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6. W. French Anderson. "Human Gene Therapy: Why Draw a Line?," Journal of Medicine and
Philosophy 14 (1989), 681-93.
7. See, for example, Kenneth M. Ludmerer, Genetics and American Society (Baltimore, MD:
The Johns Hopkins University Press, 1972), and Daniel J. Kevles, In the Name of
Eugenics (New York: Alfred A. Knopf, 1985).
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